NM_002834.5:c.179G>T

Variant names:

• chr12-112450359-G-T
• rs397507509
• NM_002834.5:c.179G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.179G>T​(p.Gly60Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.99
• Publications: 76 publications found

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450358-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 12-112450359-G-T is Pathogenic according to our data. Variant chr12-112450359-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.179G>T	p.Gly60Val	missense	Exon 3 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.179G>T	p.Gly60Val	missense	Exon 3 of 16	NP_001317366.1
	PTPN11	NM_001374625.1		c.176G>T	p.Gly59Val	missense	Exon 3 of 16	NP_001361554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.179G>T	p.Gly60Val	missense	Exon 3 of 16	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.179G>T	p.Gly60Val	missense	Exon 3 of 15	ENSP00000489597.1
	PTPN11	ENST00000392597.5	TSL:1	c.179G>T	p.Gly60Val	missense	Exon 3 of 11	ENSP00000376376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:5

Apr 09, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Our laboratory reported dual molecular diagnoses in PTPN11 (NM_002834.3, c.179G>T) and SHH (NM_000193.2, c.1284delC) in one individual with reported features of global developmental delay, hearing loss, hypotonia, hypertonia/spasticity, possible seizures, dysmorphic features (low frontal hairline, frontal bossing, deep set eye, downslanting palpebral fissures, broad based nose, upturned nasal tip), short 5th fingers, macrocephaly, structural brain abnormalities (agenesis of corpus callosum, large post interhemispheric cyst), possible cortical vision impairment, and an atrial septal defect.

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179G>T;p.(Gly60Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: ClinVar ID: 55797; PMID: 29907801; 18470943; 18701506) -.PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 30375388) - PMID: 30375388 The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain) - PM1. This variant is not present in population databases (rs397507509 , gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID:40493; 987743; 40490; 372590; 41442) - PM5. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

Aug 25, 2025

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS3, PS4, PM2, PM5, PP3

May 27, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1,PS2,PM1,PP3.

not provided Pathogenic:2

May 27, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32499245, 27923552, 18701506, 15928039, 27460089, 29296745, 32934818, 29493581, 16053901, 9491886, 11992261, 16358218, 31130284, 27959697, 33249554, 30050098)

Jul 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.179G>T; p.Gly60Val variant (rs397507509) is reported in the literature in multiple individuals affected with Noonan syndrome (Leach 2019, Monies 2006, Posey 2017). This variant is also reported in ClinVar (Variation ID: 55797) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Ala, Cys, Ser) have been reported in individuals with Noonan syndrome and are considered pathogenic (Bertelloni 2013, Limal 2006). Computational analyses predict that this variant is deleterious (REVEL: 0.931). Based on available information, this variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. PMID: 23624134. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. PMID: 29907801. Limal JM et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. PMID: 16263833. Monies D et al. Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Am J Hum Genet. 2019 Jun 6;104(6):1182-1201. PMID: 31130284. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697.

LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Jan 04, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See cases Pathogenic:1

Feb 27, 2019

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS2,PM1,PM2,PP3,PP5

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Sep 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Pathogenic:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the PTPN11 protein (p.Gly60Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 55797). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 30375388). This variant disrupts the p.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 16643459, 17020470, 24039098, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.79		Gain of ubiquitination at K55 (P = 0.095)
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397507509; hg19: chr12-112888163; COSMIC: COSV61005028; COSMIC: COSV61005028;